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PHENFORMIN AND RELATED DRUGS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Phenformin is a biguanide oral hypoglycemic agent.
    B) Refer to "METFORMIN AND RELATED AGENTS" management for further information.

Specific Substances

    1) PHENFORMIN
    2) B-PEBG
    3) DBI
    4) Fenformin
    5) Fenormin
    6) PEDG
    7) PFU
    8) Phenethylbiguanide
    9) Phenethyldiquanate
    10) N-B-phenethylformanidinyliminourea
    11) W-32

Available Forms Sources

    A) FORMS
    1) NOTE: Phenformin was removed from the US market in October 1977 because of unacceptably high risk of lactic acidosis.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Severe lactic acidosis with a fatality rate up to 50% has been associated with chronic therapeutic use, chronic excessive use, and acute overdose of biguanide hypoglycemic agents. It is most commonly associated with phenformin, and has occurred in patients taking phenformin at therapeutic doses without significant medical problems other than diabetes.
    B) Lactic acidosis has less commonly been reported in patients taking therapeutic or chronic excessive doses or acute overdoses of metformin or buformin. The majority of these patients have had significant underlying medical problems such as acute or chronic renal insufficiency, liver disease, sepsis, myocardial infarction or congestive heart failure. Refer to "METFORMIN" management for further information.
    C) Nausea and vomiting, hypoglycemia, acute renal failure, mental status depression and hypotension may develop in patients with severe biguanide associated lactic acidosis.
    0.2.5) CARDIOVASCULAR
    A) Hypotension, myocardial infarction, and tachycardia or bradycardia have been reported.
    0.2.6) RESPIRATORY
    A) Kussmaul type respirations (deep, rapid) may be noted.
    0.2.7) NEUROLOGIC
    A) CNS depression, confusion, coma, and abnormal reflexes have been reported.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting, anorexia, diarrhea, abdominal pain and occasionally gastrointestinal bleeding may develop.
    0.2.11) ACID-BASE
    A) Severe lactic acidosis has been reported with therapeutic use and overdose of biguanide hypoglycemic agents.
    0.2.16) ENDOCRINE
    A) Severe hypoglycemia may develop.
    0.2.20) REPRODUCTIVE
    A) In an in vitro study of mouse embryogenesis, phenformin produced dose dependent embryolethality and growth retardation and was associated with malformations including neural tube defects.

Laboratory Monitoring

    A) Plasma phenformin levels are not clinically useful.
    B) Monitor fluid and electrolyte balance and blood glucose carefully, monitor arterial blood gases in symptomatic patients. Determine plasma lactic acid levels in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    C) HYPOGLYCEMIA should be treated with IV glucose (ADULT: Administer 50 milliliters of 50% glucose solution; CHILD - Administer 0.5 gm/kg/dose).
    D) ACIDOSIS - Untreated lactic acidosis may result in confusion, hypotension, coma and circulatory collapse. Severe metabolic acidosis (arterial pH less than 7.1) should be corrected with IV sodium bicarbonate (a reasonable starting dose is 1 to 2 mEq/kg). Monitor blood gases to guide bicarbonate therapy.
    E) HEMODIALYSIS MAY BE USEFUL in restoring acid base and fluid and electrolyte balance and should be considered in those patients who continue to deteriorate despite conventional therapy.
    F) INSULIN/DEXTROSE - Therapy with intravenous insulin and glucose has been associated with a lower mortality rate than therapy with bicarbonate or dialysis.

Range Of Toxicity

    A) The minimal acute toxic dose is not well established in the literature.
    B) Lactic acidosis has been reported in patients whose daily dose of phenformin was increased from 100 mg to 150 mg daily. Renal disease, liver disease, cardiovascular disease, hypothyroidism, and alcohol consumption may increase the severity of toxicity.

Clinical Effects

Summary Of Exposure

    A) Severe lactic acidosis with a fatality rate up to 50% has been associated with chronic therapeutic use, chronic excessive use, and acute overdose of biguanide hypoglycemic agents. It is most commonly associated with phenformin, and has occurred in patients taking phenformin at therapeutic doses without significant medical problems other than diabetes.
    B) Lactic acidosis has less commonly been reported in patients taking therapeutic or chronic excessive doses or acute overdoses of metformin or buformin. The majority of these patients have had significant underlying medical problems such as acute or chronic renal insufficiency, liver disease, sepsis, myocardial infarction or congestive heart failure. Refer to "METFORMIN" management for further information.
    C) Nausea and vomiting, hypoglycemia, acute renal failure, mental status depression and hypotension may develop in patients with severe biguanide associated lactic acidosis.

Vital Signs

    3.3.3) TEMPERATURE
    A) HYPOTHERMIA is common in patients who develop CNS depression associated with phenformin induced acidosis (Davidson et al, 1966; Luft et al, 1978; Larcan et al, 1979; McGuinness & Talbert, 1993; Gan et al, 1992).
    3.3.4) BLOOD PRESSURE
    A) HYPOTENSION - Hypotension has been reported with severe phenformin toxicity (Bingle et al, 1970; Luft et al, 1978; McGuinness & Talbert, 1993; Larcan et al, 1979; Pashley & Felix, 1972).

Heent

    3.4.3) EYES
    A) MYDRIASIS - Fixed dilated pupils have been reported in patients with hypoglycemia and coma from phenformin overdose (Bingle et al, 1970; Larcan et al, 1979).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypotension, myocardial infarction, and tachycardia or bradycardia have been reported.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Hypotension has been reported with severe phenformin toxicity (Bingle et al, 1970; Luft et al, 1978; McGuinness & Talbert, 1993; Larcan et al, 1979; Pashley & Felix, 1972).
    B) TACHYARRHYTHMIA
    1) Sinus tachycardia has been reported in patients with hypotension or recurrent vomiting from biguanide toxicity (Dobson & Houston, 1965; (Davidson et al, 1966; Larcan et al, 1979).
    C) BRADYCARDIA
    1) Bradycardia and hypotension were reported in a 64-year-old man with severe phenformin-induced acidosis (McGuinness & Talbert, 1993).
    D) MYOCARDIAL INFARCTION
    1) Myocardial infarction may develop in patients with biguanide induced lactic acidosis. In a series of 330 patients with biguanide induced acidosis, 4 were diagnosed with myocardial infarction at the time lactic acidosis was diagnosed and 13 sustained myocardial infarction during treatment of the acidosis (Luft et al, 1978).

Respiratory

    3.6.1) SUMMARY
    A) Kussmaul type respirations (deep, rapid) may be noted.
    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) KUSSMAUL'S RESPIRATION - Deep, rapid breathing has been reported in patients with biguanide-induced lactic acidosis (Bingle et al, 1970; Luft et al, 1978; Davidson et al, 1966).
    B) ACUTE LUNG INJURY
    1) Pulmonary edema developed in an adult diabetic who ingested 1500 mg of phenformin (Bingle et al, 1970).

Neurologic

    3.7.1) SUMMARY
    A) CNS depression, confusion, coma, and abnormal reflexes have been reported.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) Lethargy and fatigue have been reported (Dobson & Houston, 1965; (Luft et al, 1978; Ilson et al, 1990). Coma is usually associated with hypoglycemia and/or severe acidosis (Davidson et al, 1966; Bingle et al, 1970; Larcan et al, 1979).
    B) HYPOREFLEXIA
    1) Abnormal reflexes including loss of corneal reflexes and pupillary response to light, extensor plantar reflexes, and decreased deep tendon reflexes have been reported in patients with coma from biguanide toxicity (Davidson et al, 1966; Bingle et al, 1970; Larcan et al, 1979).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting, anorexia, diarrhea, abdominal pain and occasionally gastrointestinal bleeding may develop.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) Severe nausea, vomiting and diarrhea may be the principal effects after acute overdose (Dobson, 1965).
    2) Nausea, vomiting, diarrhea and abdominal pain may occur in patients with lactic acidosis associated with biguanide therapy (Luft et al, 1978; McGuinness & Talbert, 1993; Gan et al, 1992).
    B) GASTROINTESTINAL HEMORRHAGE
    1) Gastrointestinal bleeding has been reported after acute overdose (Bingle et al, 1970) and in patients with lactic acidosis from chronic therapy (Pashley & Felix, 1972).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) Acute renal failure may develop in patients with severe biguanide associated lactic acidosis and hypotension (Luft et al, 1978; McGuinness & Talbert, 1993).

Acid-Base

    3.11.1) SUMMARY
    A) Severe lactic acidosis has been reported with therapeutic use and overdose of biguanide hypoglycemic agents.
    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDOSIS
    1) PHENFORMIN -
    a) Severe lactic acidosis has been reported after chronic therapeutic use of phenformin (Luft et al, 1978; Ilson et al, 1990) McGiunness & Talbert, 1993), chronic excessive dosing (Pashley & Felix, 1972) and acute overdose (Davidson et al, 1966; Bingle et al, 1970; Larcan et al, 1979).
    b) Phenformin induced lactic acidosis has been reported in many patients with or without normal renal function, and is associated with a fatality rate of up to 50% (Luft et al, 1978; Bergman et al, 1978). Factors associated with a poor prognosis include age over 60 years, shock, more severe lactic acidosis at the time of diagnosis (pH less than 7.0) and possibly impaired renal function (Luft et al, 1978).
    c) It has been postulated that lactic acidosis is most likely in those patients who fail to metabolize (ie hydroxylation defect) phenformin adequately (Bosisio et al, 1981).
    d) Although phenformin is not marketed in the United States, cases of phenformin-associated lactic acidosis may be observed. A 67-year-old male presented to an ED in New York City with symptoms of lactic acidosis after taking phenformin obtained in China (Lu et al, 1996). Another patient presented with lactic acidosis in Massachusetts after taking a combination product of chlorpropamide and phenformin obtained in Haiti (Rosand et al, 1997).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) Extreme neutrophil leukocytosis (60,000/mm(3)) was reported in one fatal overdose (Bingle et al, 1970).

Endocrine

    3.16.1) SUMMARY
    A) Severe hypoglycemia may develop.
    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) Severe hypoglycemia may develop after acute overdose in diabetic or non-diabetic patients (Davidson et al, 1969; (Larcan et al, 1979).
    2) Hypoglycemia may also develop in patients with biguanide associated lactic acidosis (Bingle et al, 1970; Luft et al, 1978).

Reproductive

    3.20.1) SUMMARY
    A) In an in vitro study of mouse embryogenesis, phenformin produced dose dependent embryolethality and growth retardation and was associated with malformations including neural tube defects.
    3.20.2) TERATOGENICITY
    A) CNS CONGENITAL ANOMALY
    1) In an in vitro study of mouse embryogenesis, phenformin produced dose dependent embryolethality and growth retardation and was associated with malformations including neural tube defects (Denno & Sadler, 1994).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma phenformin levels are not clinically useful.
    B) Monitor fluid and electrolyte balance and blood glucose carefully, monitor arterial blood gases in symptomatic patients. Determine plasma lactic acid levels in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, blood glucose, and acid base status.
    2) In patients with significant acidosis follow serial blood gases, electrolytes, renal function tests, blood glucose and lactate levels.
    B) ACID/BASE
    1) Monitor acid base status.
    4.1.3) URINE
    A) OTHER
    1) Monitor urine output in patients with significant acidosis.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Institute continuous cardiac monitoring and obtain an ECG in patients with significant metabolic acidosis.
    b) In patients with a significant acidosis search for a precipitating event such as infection, myocardial infarction, hepatic or renal insufficiency.

Methods

    A) CHROMATOGRAPHY
    1) There are HPLC methods described for determination of phenformin in plasma (Benzi et al, 1986; Marchetti et al, 1987).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Plasma phenformin levels are not clinically useful.
    B) Monitor fluid and electrolyte balance and blood glucose carefully, monitor arterial blood gases in symptomatic patients. Determine plasma lactic acid levels in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS
    1) Nausea and vomiting are likely to occur shortly following substantial ingestions.
    2) Because of the risk of CNS depression from hypoglycemia in these patients, activated charcoal is preferable to ipecac-induced emesis.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) ACIDOSIS
    1) Untreated patients with lactic acidosis may develop confusion, hypotension, coma, and circulatory collapse.
    2) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
    3) Monitor serum sodium to avoid overload.
    B) HYPOGLYCEMIA
    1) Should be treated with IV dextrose. Usually 0.5 gram/kilogram/dose in children and 50 milliliters of 50% glucose solution in adults.
    C) MONITORING OF PATIENT
    1) Monitor arterial blood gases carefully.
    2) Monitor fluid load, potassium, sodium, and bicarbonate.
    D) INSULIN (CLASS)
    1) In a review of 306 cases of phenformin-associated lactic acidosis, patients treated with intravenous insulin (10 to 20 units every 4 hours on average) and dextrose (5 to 12.5 grams every 4 hours on average) had a greater survival rate (21 of 26 patients; 81%) than those treated with bicarbonate (50 of 306 patients; 49%) or dialysis (16 of 31 patients; 52%) (Misbin, 1977).
    E) HEMODIALYSIS
    1) Effective in restoring acid-base balance toward normal and also to normalize potassium, sodium and fluid balance.
    2) Lactic acidosis associated with biguanide therapy has been treated with sodium bicarbonate hemodialysis, with rapid improvement in the acid base status (Larcan et al; 1979; Chalopin et al, 1984; (Lalau et al, 1987).
    F) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Lactic acidosis associated with biguanide therapy has been treated with sodium bicarbonate hemodialysis, with rapid improvement in the acid base status (Larcan et al; 1979; Chalopin et al, 1984; (Lalau et al, 1987).

Abstracts

Case Reports

    A) ADVERSE EFFECTS
    1) A 44-year-old diabetic woman ingested 1500 mg of sustained-release phenformin.
    2) Nausea and vomiting developed promptly and persisted for 18 hours. Upon arrival to the hospital 24 hours postingestion she was hypotensive, comatose, hypoglycemic (blood sugar less than 25 mg%), and severely acidotic (serum CO2 3 mEq/L).
    3) After slight correction of acidemia by administration of sodium bicarbonate (arterial pH increased to 6.97), hypotension and pulmonary edema occurred rapidly. The patient died 30 hours postingestion (Bingle et al, 1970).
    4) Extensive gastrointestinal mucosal hemorrhage was found on autopsy.
    B) ADULT
    1) Ingestion of 870 mg of phenformin (sustained-release) by a 47-year-old diabetic woman resulted in abdomonal pain, cramping and explosive vomiting within one hour, which recurred within two hours.
    2) She reported staggering gait, lethargy, and sweating 4 to 5 hours after ingestion. Laboratory data on admission 8 hours postingestion included a blood sugar of 126 mg%, blood lactic acid 0.9 mmol/L, and a blood pressure of 180/110.
    3) Gastrointestinal symptoms resolved within 6 to 7 hours after ingestion (Dobson, 1965).

Range Of Toxicity

Summary

    A) The minimal acute toxic dose is not well established in the literature.
    B) Lactic acidosis has been reported in patients whose daily dose of phenformin was increased from 100 mg to 150 mg daily. Renal disease, liver disease, cardiovascular disease, hypothyroidism, and alcohol consumption may increase the severity of toxicity.

Minimum Lethal Exposure

    A) CASE REPORTS
    1) ADULT
    a) Ingestion of 1500 milligrams of sustained-release phenformin resulted in death 30 hours postresection in an adult diabetic (Bingle et al, 1970).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) CHRONIC - There have been cases of lactic acidosis reported when phenformin was increased from 100 to 150 milligrams daily. The severity of toxicity was frequently dependent upon other underlying problems (e.g., renal failure, liver disease, cardiovascular disease, hypothyroidism, and alcohol consumption).
    B) CASE REPORTS
    1) ADULT
    a) A 47-year-old diabetic woman who ingested 850 milligrams of phenformin developed gastroenteritis with no evidence of hypoglycemia (Dobson, 1965).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) PHENFORMIN -
    1) The usual therapeutic plasma level is between 28 and 114 ng/ml (Marchetti et al, 1987).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) PHENFORMIN -
    1) A blood phenformin level of 3 mcg/ml was reported on autopsy of a 44-year-old woman who died after acute phenformin overdose (Bingle et al, 1970).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Phenformin does not stimulate secretion of insulin. There are many proposed mechanisms of action, including 1. increased cell uptake of glucose; 2. decreased gluconeogenesis; 3. increase in the turnover rate of glucose; 4. inhibition of glucose absorption.

Toxicologic Mechanism

    A) Animal studies indicate that Ca(2+) may have a role in the toxicity of phenformin.
    B) Hyperlactatemic and hypoglycemic effects in vivo may be due to impaired ATP production arising from inactivation of Ca(2+)-sensitive NAD(+)-dependent mitochondrial dehydrogenases due to alteration in mitochondrial calcium content by interaction of phenformin with mitochondrial membranes.
    C) The elevated blood lactate concentrations may be due to the hypoglycemic effect (Gettings et al, 1988).
    D) In diabetics insulin deficiency may predispose to lactic acidosis by causing an inhibition of pyruvate dehydrogenation and lactate oxidation (Misbin, 1977). NAD supplies are diminished by depressed mitochondrial respiration and increased fatty acid metabolism. Reduced NAD production in turn causes lactic aid accumulation secondary to anaerobic metabolism. Phenformin use may exacerbate this situation by inducing alterations in lactate metabolism.

References

General Bibliography

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